The selective tachykinin NK1 receptor agonists, septide ([Glp6,Pro9]substance P-(6-11)) and [Sar9]substance P sulfone, both produced concentration-dependent contraction of the circular muscle of the guinea-pig ileum (EC50 values 36 and 84 pM, respectively). The potent and selective NK1 receptor antagonist (+/-)-CP 96,345 antagonized the response to septide with significantly higher affinity than it did the response to [Sar9]substance P sulfone (pA2 values 9.24 and 8.17, respectively) without modifying the response to the selective NK2 receptor agonist, [beta-Ala8]neurokinin A-(4-10). These findings indicate that the septide-sensitive receptor in the circular muscle of the guinea-pig ileum is recognized with high affinity by the NK1 receptor selective antagonist (+/-)-CP 96,345.